Migraine is a huge clinical problem affecting over 25 million Americans and costing billions of dollars. Episodic migraine is a recurrent headache that occurs 1-14 days per month. It may occur with or without aura (focal neurological symptoms that usually develop and resolve). Most (80-95%) migraine patients remain episodic with low frequency attacks (1-4 attacks per month) throughout their lives whereas some (about 5%) progress from low to high frequency and then to daily headache/migraine. One of the unsolved mysteries of the disease is the nature of how the brain changes in progressing from the low frequency (LF) episodic manifestation to the more frequent high frequency (HF) or chronic daily headache. Here we propose to evaluate functional, morphometric (gray matter volume and white matter integrity) and chemical (measures of excitatory and inhibitory metabolites) changes in the brains of separate cohorts of LF and HF acute episodic migraineurs. Specifically we will compare these three brain measures in (1) LF migraineurs with and without aura with healthy age, gender, education level, matched controls;(2) HF migraineurs with and without aura with healthy age, gender, education level, matched controls;and (3) LF with HF migraineurs with and with out aura. We wish to test the hypothesis that with increased migraine frequency, increased excitatory amino acids and decreased inhibitory amino acids lead to alterations in brain structure and function. We have the necessary expertise in imaging, migraine neurobiology and neurology, and preliminary data for each aspect of the proposed research. PUBLIC HEALTH RELEVANCE: Using functional imaging techniques, the proposed research will evaluate and compare the structure, chemistry and function of brains of patients with migraine who suffer a relatively few attacks (low frequency) per month compared with those who suffer more than 10 attacks per month (high frequency). Given the burden of repeated migraine attacks, any effort to understand better the reasons for its progression may offer clues for novel therapeutic approaches and hope for prevention of disease progression in those who are not affected yet.